Primitive childhood tumors (i.e., classically Ewing's sarcoma, neuroblastoma, lymphoma, and soft tissue sarcoma), are frequently morphologically indistinguishable. Ultrastructural and immunocytochemical techniques are useful but not infallible. Monoclonal antibodies (MoAbs) which recognize neural, lymphoid (HLA-related), and tissue-specific determinants might be useful in distinguishing these entities. We have studied more than 20 cells lines by flow cytofluorometry and more than 40 tumors by frozen section immunocytochemistry with a panel of 12 MoAbs and find reproducible patterns of reactivity which serve to reliably distinguish all neural tumors and hematopoietic malignancies. Ewing's sarcoma is similar to rhabdomyosarcoma, but shows some reactivity with certain neural MoAbs. Peripheral neuroepithelioma is a unique tumor with reactivity intermediate between sarcomas and neural tumors, not unlike Ewing's sarcoma. Thus, most of the tumors are readily recognized, even in the absence of any distinguishing morphologic characteristic. These results have important diagnostic and therapeutic implications, but further study of more tumors is required.